Lp(a) and Aortic Valve Calcification

Brief description of study

Aortic valve stenosis (AVS), the most common form of valve disease in the western world,
afflicts more than 1 million individuals in North America [1] and the burden of AVS is high
and is expected to double within the next 50 years [2]. Medical therapy to prevent
development or reduce progression of AVS is currently not available and the only effective
treatment for AVS is aortic valve replacement, for which costs have been estimated up to
120,000$ [3,4]. Recently, we and others have identified rs10455872 at the LPA locus as a
susceptibility single nucleotide polymorphism (SNP) for aortic valve calcification (AVC) and
AVS [5,6] and rs10455872 is associated with elevated plasma lipoprotein (Lp)(a) levels [7].
Lp(a) is a LDL-like particle consisting of hepatically synthesized apolipoprotein B-100 that
is noncovalently bound to the plasminogen-like glycoprotein apolipoprotein(a) [8]. Lp(a)
promotes atherosclerotic stenosis, and possibly thrombosis, and has been hypothesized to
contribute to wound healing, each of which could explain an association with AVS [9,10].
Lp(a) is relatively refractory to both lifestyle and drug intervention, with only nicotinic
acid and monoclonal antibody inhibition of the proprotein convertase subtilisin/kexin type 9
that have showed reductions in Lp(a) levels [11,12]. However, the evidence that patients with
AVS could be characterized by high Lp(a) levels is scarce. Glader et al. [13] showed that
plasma levels of Lp(a) were almost 1.5-fold higher in 101 patients with AVS compared to
matched controls, although this relationship did not reach statistical significance.
Subsequent studies have also reported an association between elevated plasma Lp(a) levels and
higher prevalence of AVS. More specifically, Kamstrup and colleagues [14] reported that
elevated Lp(a) levels and corresponding genotypes were associated with increased risk of AVS
in the general population with levels >90 mg/dL predicting a threefold increased risk. We
have measured Lp(a) and oxidized phospholipids plasma levels in 220 patients with
mild-to-moderate calcific AVS enrolled in the Aortic Stenosis Progression Observation:
Measuring Effects of Rosuvastatin (ASTRONOMER) trial [15]. Results of this study suggest that
high Lp(a) and oxidized phospholipids both predict calcific AVS progression, especially in
younger patients with calcific AVS. We also found that statin therapy considerably increased
both Lp(a) and oxidized phospholipids levels. Whether the fact that statins increase these
risk factors for calcific AVS might explain at least to a certain extent why statins failed
to promote calcific AVS regression or stabilization in at least four trials, including
ASTRONOMER.